ABSTRACT Recent studies suggest that the prevalent condition of chronic short sleep (CSS) may be a key modifier of Alzheimer disease (AD). Specifically, sleep disruption increases brain amyloid beta (A?) and amyloid plaque in mouse models of AD and increases A? in cerebrospinal fluid in humans, while poor sleep in older humans predicts poor memory consolidation and increased amyloid plaque burden. We recently discovered that chronic short sleep (CSS) in mice increases A? in brain regions that are most vulnerable in AD, including the hippocampus, and results in synapse loss and gliosis in these regions. Amyloid precursor protein knock-in (APPKI) mice with the NL mutation under rested conditions do not exhibit increased A?, gliosis, or cognitive impairment. Yet we find in preliminary studies that the APPKI NL mice exposed to CSS do show increased A?, gliosis, loss of hippocampal synapses and A?-dependent hippocampal memory impairment, suggesting that CSS in the APPKI NL mouse provides an excellent model in which to examine the molecular mechanisms of CSS-provoked early AD neural injury. Intriguingly, hippocampal regions affected by CSS in APPKI NL mice show increased APOE, while APOE2 targeted replacement (TR) mice have far less neural injury in response to CSS. We hypothesize that even before amyloid plaque development, CSS-increased A? underlies synapse loss and hippocampal memory decline. We plan to use double KI mice (APP-NL/APOE-TR) to: (1) test the role of the APOE2 isoform on the temporal progression of hippocampal-dependent cognitive decline relative to the temporal course of hippocampal cholesterol, APOE and A? responses; (2) understand APOE2 interactions in the temporal progression of microglial and complement responses following CSS, with relevance to hippocampal synapse loss; and (3) determine the protective capacity of APOE2 in reducing astrocyte SerpinA3 up-regulation and its role in neuronal loss in early AD. Collectively, the work defines early events in the novel CSS-provoked AD model and comprehensively tests the potential of APOE2 in protection from key pathogenic elements in AD under basal conditions of aging and in response to the chronic metabolic stress of CSS.